Cancer is a group of diseases characterized by uncontrolled proliferation of aberrant, undifferentiated cells (tumor formation) which may spread throughout the body to invade other tissues (metastasis). Mutations in oncogenes, tumor-suppressor genes and stability genes may contribute to the development of a cancer by promoting cell division and growth and inhibiting cell death or cell-cycle arrest (Vogelstein et al. (2004) Nature Med., 10:789-799). No single gene defect is the sole cause of any cancer, necessitating a detailed understanding of the biology of each different cancer type for the development of effective, cancer-specific treatments.
Cancer treatment options were limited to surgery to remove the tumor mass before 1950, while ionizing radiation therapy was introduced in the 1960's. However, neither of these treatments can reach every organ of the body to eradicate metastatic cancers. Therefore, chemotherapy has become a focus in cancer treatment (Chabner et al. (2005) Nat. Rev. Cancer, 5:65-72). Natural products are the ultimate source of 62-67% of the agents in clinical trial for the treatment of cancer (Newman et al. (2007) J. Nat. Prod., 70:461-477). At the end of 2006, there were 185 anticancer drugs available in the West and Japan, of which only 24% (42) were wholly synthetic agents. Of the remaining 76%, 25 (14%) were unmodified natural products, 48 (28%) were modified natural products, 40 (23%) were based on a natural product pharmacophore or mimic natural products and 20 (11%) were “biological” (e.g., proteins) and vaccines (Newman et al. (2007) J. Nat. Prod., 70:461-477). These compounds used alone or in combination with surgery or radiation have had varied success as is reflected in the comparable USA cancer death rates for 1950 and 2005, which is in sharp contrast to the dramatically reduced 2005 death rates attributed to heart diseases, cerebrovascular diseases and pneumonia/influenza (Amer. Cancer Soc. (2008) Cancer Statistics www.cancer.org/docroot/PRO/content/PRO—1—1_Cancer_Statistics—2008_Presentation.asp). Even in the USA, approximately only 50% of all individuals afflicted with any cancer attain long term survival (Brenner, H. (2002) The Lancet, 360:9340). Accordingly, there is a need in the art to isolate and purify novel, potent cancer chemotherapeutic agents.
Two modified natural products were recently approved (2007) as cancer treatments: ixabepilone (analog of Myxobacterium-derived epothilone B, Ixempra®) for advanced metastatic breast cancer (Moulder (2008) Future Oncology, 4:333-340) and temsirolimus (derivative of rapamycin from Streptomyces hygroscopicus, Torisel®) for advanced renal cancer (Simpson and Curran (2008) Drugs, 68:631-638). Examples of natural products or natural product derivatives in current cancer clinical trials (www.cancer.gov/clinicaltrials) with the National Cancer Institute are FR901228 (from Chromobacterium violaceum), bryostatin-1 (from marine bryozoan Bugula neritina) and 17-AAG (analog of geldanamycin from Streptomyces hygroscopicus). Marine organisms continue to yield a diverse array of biologically active molecules, a remarkable number of which are peptide-based cancer cell toxins of putative microbial symbiont biogenesis (Simmons et al. (2008) Proc. Natl. Acad. Sci., 105:4587-4594). Development of these as anticancer drugs has met with some success (Rawat et al. (2006) Med. Chem., 6:33-40). Indeed, there are as many as 50 marine-derived natural products or derivatives in clinical and preclinical trials (Newman et al. (2004) J. Nat. Prod., 67:1216-1238). Ecteinascidin 743 (from the tunicate Ecteinascidia turbinata) and Neovastat (from a shark) have progressed to phase III trials where they are being used to treat larger numbers of people. Ecteinascidin 743 (YONDELIS®, trabectedin) is a tetrahydroisoquinolone alkaloid that binds DNA by a novel mechanism, and is being developed by the Spanish company PharmaMar for the treatment of soft tissue sarcomas (Fayette et al. (2006) Curr. Opin. Oncol., 18:347-353). Neovastat (AE941) is an extract of shark cartilage with potent anti-angiogenic activity in phase III trials for lung and renal carcinoma (Gingras et al. (2002) Anti-Cancer Drugs, 14:91-96), and has recently been elucidated as immunoglobulin kappa light chain (28 kDa protein; Boivin et al. (2004) Arch. Biochem. Biophys., 431:197-206). Further, ascidian-derived dihydrodidemnin B (Aplidin®) has orphan drug status for the treatment of multiple myeloma and acute lymphoblastic leukemia; the green algal isolate kahalalide F has also reached phase II clinical trials.
The Cyanobacteria (blue-green algae) are an ancient group of opportunistic, often toxic colonial organisms, which commonly show spatial and temporal variation in biomass and may indicate shallow reef damage or stagnant waters. The majority of marine cyanobacterial metabolites reported to date has been isolated from the genus Lyngbya and are products of mixed peptide and ketide biosynthesis. This structural class has been a rich source of lead compounds in the development of treatments for cancer (Gerwick, et al. (2001) In: Alkaloids: Chemistry and Biology. Cordell, Ga. (Ed). Academic Press: N.Y. Vol. 57, pp 75-184; Tan, L. T. (2007) Phytochem., 68:954-979), and includes the antimitotic agents curacin A, dolastatins 10 and 15, and cryptophycins (Newman et al. (2004) J. Nat. Prod., 67:1216-1238). Synthetic analogs of curacin A and dolastatins 10 and 15 are in preclinical and clinical trials, respectively. Indeed, TZT-1027, a synthetic analogue of the cyanobacterial metabolite dolastatin 10, has reached phase II clinical trials. The high degree of N-methylation of many of these cyanobacterial peptides may improve their suitability as a drug since N-methylation has been shown to improve pharmacological parameters such as lipophilicity, proteolytic stability, and duration of action, properties for which regular peptides are notoriously poor and which limits their bioavailability (Loffert, A. J. (2002) Pept. Sci., 8:1-7; Morishita et al. (2006) Drug Discovery Today, 11:905-910).